The initial goal of Project 4 is the development of a new drug for cancer treatment based upon finding a pharmacologically acceptable, potent, and selective inhibitor of the polyamine biosynthetic pathway enzyme S-adenosylmethionine decarboxylase (AdoMetDC). As the project evolves, attention will be given to other relevant polyamine pathway enzymes, as well. With regard to AdoMetDC, Project 4 will be involved in the design and synthesis of a series of different classes of compounds that be evaluated as inhibitors of the enzyme. These different classes of compounds either have been or will be designed based upon existing literature data from our laboratory and others, the structural data provided by Dr. Ealick's laboratory (Project 2), and the modeling input from Dr. Guida's laboratory (Project 3). Initial targets will be in the nucleoside class, and will focus on exploring interactions of C-5' chain-extended ribonucleosides in all areas of the active site. Specifically, modifications will be made: 1) On the adenine ring, where we will explore groups that will favor a syn conformation of the nucleoside prior to entry into the active site; 2) On the chain extension, where we will explore interactions with the residues between the carbohydrate and the pyruvate prosthetic group, including several hydrophobic residues, as well as a cysteine, and a histidine; and 3) On the area surrounding the carboxylic acid binding site where the decarboxylation occurs. Based upon input from Drs. Ealick and Guida, we will be designing and synthesizing various non-nucleoside inhibitors with enhanced potency and selectivity based upon the already solved structure of the AdoMetDC complex with the clinical agent SAM486A. Finally, other potential inhibitors will be designed, again in collaboration with Drs. Ealick and Guida, based upon de novo modeling data and based upon the possible involvement of the putrescine-binding site of the enzyme. All compounds will be examined in Dr. Pegg's laboratory (Project 1) for their biological activity in the relevant systems. Based upon the biological results from Dr. Pegg's laboratory, certain target compounds will be selected for evaluation in animal models in Core B (Dr. Waud). Compounds with robust animal activity and other favorable characteristics will be considered for further development. Biological, structural, and modeling feedback will be used in evaluating our proposed target inhibitors and for the design of new proposed inhibitors. Regular interaction between the four project leaders will facilitate the design new targets and the establishment of synthetic priorities. We expect that one or more clinical candidates will derive from our efforts as the project advances.